University of California San Francisco
Helen Diller Family Comprehensive Cancer Center

For Children With Brain Tumors, Next-Generation Sequencing May Lead to Different Diagnoses

UCSF Study Shows Profiling Offers Clues About Parents’ Own Risks for Other Cancers

By Suzanne Leigh | | November 15, 2016

For Children With Brain Tumors, Next-Generation Sequencing May Lead to Different Diagnoses

Next-generation sequencing for patients at UCSF Medical Center is prompting changes in brain tumor diagnoses for some children and a retooling of treatment plans in many cases. Sequencing is also providing valuable insights to some parents about their own susceptibility to other seemingly unrelated cancers.

In a groundbreaking study published in the journal Neuro-Oncology on Nov. 14, 2016, UCSF clinical investigators chronicled the results of sequencing a panel of 510 cancer-associated genes in brain tissue and blood samples from 31 pediatric patients whose brain tumors were high grade, treatment-resistant or had ambiguous features.

Sequencing is conducted at UCSF Clinical Cancer Genomics Laboratory, one of the few hospital facilities nationwide that clinically profiles tumor and compares it with the patient’s normal tissue, identifying any mutations driving tumor growth and matching them with targeted therapies.

Brain tumors are now the number one cause of cancer death in children, according to the Centers for Disease Control and Prevention. Pediatric brain tumor deaths have increased slightly since 1999, while fatalities in leukemia, the most common childhood cancer, have declined.

In the study, investigators compared the initial diagnosis based on the pathologist’s microscopic findings – which looked at features like cell morphology, rate of cell division and tumor invasiveness – to genetic alterations identified by molecular pathologists, who specialize in brain tumor genetics.

Different Diagnosis For 6 Patients

While sequencing confirmed the pathology report in 25 of the 31 patients, the remaining six children had their diagnoses changed as a result of genetic findings. In one remarkable case, a 9-year-old had already started aggressive treatment after her tumor was classified as being of “indeterminate grade” with imaging features “suggestive of a high-grade infiltrative tumor.” Sequencing revealed that the tumor was nonmalignant and since the likelihood of recurrence was low, chemotherapy was stopped.

“In this era of precision medicine, we’re changing the paradigm of diagnosis and treatment,” said senior and corresponding author David Solomon, MD, PhD, assistant professor in the Department of Pathology at UCSF Medical Center. “I don’t think genomic profiling is going to replace the role of the pathologist looking at tissue under the microscope. What we’re now achieving using the UCSF500 Cancer Gene Panel is integrating the results of genomic profiling together with the histologic features seen under the microscope to produce the most accurate diagnosis possible for children with brain tumors.”

In 19 of the 31 patients, the investigators identified genetic alterations that were potentially targetable by existing treatments. Targeted therapies are less toxic than chemotherapy, which indiscriminately attacks both cancerous and noncancerous cells. Mutations include non-heritable somatic mutations, which are specific to the tumor, and germline mutations, those relating to childhood cancers, which are identified in the peripheral blood and found in every cell of the body.

Fewer Mutations Raise Hope For Targeted Therapies

While adult tumors typically have numerous mutations, tumors in pediatric patients may have just one or two.

“Because pediatric tumors tend to have significantly fewer genetic alterations, the hope is that targeted therapies will be more effective in children,” said Solomon, who is also an attending molecular pathologist at the UCSF Clinical Cancer Genomics Laboratory.

“We’ve currently sequenced about 60 children with brain tumors using the UCSF500 Cancer Gene Panel, and this group of cases has been particularly interesting and promising. UCSF has world-renowned neuropathology and neuro-oncology groups who are working together to make the right diagnosis, determine the tumor genetics, and either get patients on clinical trials or acquire a targeted therapy,” said first author Nancy Joseph, MD, PhD, assistant professor in the UCSF Department of Pathology, who worked on validating the UCSF500 Cancer Panel for clinical use.